We have been developing strategies to utilize nitric oxide (NO) in cancer treatment. In addition to the use of synthetic NO donors, we are researching the mechanisms that control the endogenous cellular production. We have recently discovered that inhibition of Nitric oxide synthase (NOS) given after chemotherapy or radiation treatment enhances tumor re-growth delay. Given that there are a number of clinically available NOS inhibitors this could have potential clinical applications. We have recently characterized the NO levels that are required to activate and stabilize key proteins involved in carcinongenesis, p53, ERK and HIF1-alpha. Our recent discover that NOS-2 and COX-2 are strong predictor of poor prognosis in ER negative cancer. In patient cohort we have found that 94% of the deceased had high NOS2 in ER- patients. We have been exploring the molecular mechanisms that elucidate pathways that link these biomarkers. We have found that NO has two effect: one it activates key pathways, beta-catenin, NFkappa, AP-1 and ETS. These pathways lead to increase proliferation, migration and cancer stem cell markers. These findings have provided new models to develop compounds that target this particular aggressive cancer type describe in our other work. One of the unique aspect is that NO can induce many markers that associated with poor prognosis in breast cancer. However, activation of the pathways are not enough, there has to be inhibition of tumor supressor proteins. This molecular profile points to a unique mechanism that suggest NO and NOS-2 are complete protumorigenic agent with implications in breast, colon, liver, brain, prostate, stomach and pancreatic cancer. Currently we have develop a model for ER(-) breast cancer that may be responsible for 92% of this disease. For this model we plan to develop therapies and biomarkers. In a recent survey of the literature, there is growing data that clearly show that elevated expression of NOS2 are associated with the vast majority of tumors. This model may be applicable beyond the breast cancer and may apply to numerous solid cancer (adenocarcinomas), such as glioma, pnacreatic, melenoma, cervical ovarian, prostate gastic, hepatacellular carcinomima, esphogeal, lung and colon. In most cases like ER- breast cancer predict poor outcome. We are currently identifying a variety of cancer mechanism that drive poor outcome. These models do and will provide a road map for therapy. Since nitric oxide is a powerful paradigm, this is a unique model for elucidation of new therapeutic approaches.